Feedback inhibition of calcineurin and Ras by a dual inhibitory protein Carabin

Abstract

Feedback regulation of adaptive immunity is a fundamental mechanism for controlling the overall output of different signal transduction pathways, including that mediated by the T-cell antigen receptor (TCR). Calcineurin and Ras are known to have essential functions during T-cell activation. However, how the calcineurin signalling pathway is terminated in the process is still largely unknown. Although several endogenous inhibitors of calcineurin have been reported, none fulfils the criteria of a feedback inhibitor, as their expression is not responsive to TCR signalling. Here we identify an endogenous inhibitor of calcineurin, named Carabin, which also inhibits the Ras signalling pathway through its intrinsic Ras GTPase-activating protein (GAP) activity. Expression of Carabin is upregulated on TCR signalling in a manner that is sensitive to inhibitors of calcineurin, indicating that Carabin constitutes part of a negative regulatory loop for the intracellular TCR signalling pathway. Knockdown of Carabin by short interfering RNA led to a significant enhancement of interleukin-2 production by antigen-specific T cells in vitro and in vivo. Thus, Carabin is a negative feedback inhibitor of the calcineurin signalling pathway that also mediates crosstalk between calcineurin and Ras.

A distinct population of clonogenic and multipotent murine follicular keratinocytes residing in the upper isthmus

“…6). Tbc1d10c is also named Carabin for its inhibitory roles in calcineurin and Ras signaling in the regulation of T-cell activation (Pan et al, 2007); however, the expression pattern of Tbc1d10c in skin is unknown. Tbc1d10c protein localized to the UI region in adult telogen HFs but was not detected in the bulge or infundibulum regions of the HF or the IFE (Fig.…”

Carabin Protects Against Cardiac Hypertrophy by Blocking Calcineurin, Ras, and Ca 2+ /Calmodulin-Dependent Protein Kinase II Signaling

“…In this context, Carabin (alias TBC/Rab GTPase activating protein [GAP]), a protein expressed mainly in the immune system and the heart, raised our interest. 19 Carabin has 446 amino acid residues and contains 2 important regions, a putative Ras GTPase-activating protein (GAP) domain at its amino terminus and a carboxy-terminal domain that bears a calcineurin-interacting domain. 19,20 Here, we provide the first evidence for an antihypertrophic role of Carabin in the heart.…”

Les acteurs moléculaires du remodelage cardiaque pathologique

“…Carabin fut initialement caractérisée dans le système immunitaire [37]. Cette protéine de 446 acides aminés possède deux régions importantes : une région (séquence 89-294) Ras/Rab GAP (GTPase activating protein) et une région (séquence 406-446) de liaison à la CaN dans sa partie carboxy-terminale.…”

“…Cette protéine de 446 acides aminés possède deux régions importantes : une région (séquence 89-294) Ras/Rab GAP (GTPase activating protein) et une région (séquence 406-446) de liaison à la CaN dans sa partie carboxy-terminale. Dans les cellules T et B, carabin inhibe l'activité phosphatase de la CaN et la signalisation associée à la petite protéine G, Ras et son effecteur ERK (extracellular signalregulated kinase) [37,38]. Étant donné les rôles critiques joués par ces protéines de signalisation dans la mise en place du remodelage délétère, nous avons émis l'hypothèse que carabin pourrait avoir un rôle cardioprotecteur.…”